Chemotherapy against cancer has made a remarkable progress thanks to introduction of molecular targeted pharmaceuticals. However, there are still numerous refractory cancers that cannot be overcome. For such reasons, it is desired to develop new molecular targeted agents against cancer having a higher therapeutic effect.
Phosphatidylinositol-3-kinase (hereinbelow, referred to as “PI3K”) is an enzyme which produces phosphatidyl inositol 3,4,5-triphosphate (PIP3) by phosphorylation of the phosphate group at position 3 of the inositol ring in phosphatidyl inositol 4,5-biphosphate (PIP2), which is a phospholipid present in a cell membrane (Non-Patent Document 1: Fruman et al., Annual Rev Biochem 67, 481-507, doi:10.1146/annurev. biochem. 67.1.481 (1998)). It is activated by tyrosine kinase of various growth factor receptors and, through the activation of AKT in downstream, it functions to promote survival and proliferation of cells (Non-Patent Document 2: Cantley, L. C. Science 296, 1655-1657, doi: 10.1126/science. 296.5573.1655 (2002)). PI3K is known to be involved with cancer.
PI3K forms a heterodimer consisting of a catalytic subunit and a regulatory subunit. PIK3CA gene encodes p110α, which is a catalytic subunit of Class IA PI3K. Regarding the PIK3CA gene, highly frequent gene amplification or point mutation of function developing type has been reported for various cancer types including breast cancer and colon cancer (Non-Patent Document 3: Samuels et al., Science 304, 554 (2004); Non-Patent Document 4: Ikenoue et al., Cancer Res 65, 4562 (2005); and Non-Patent Document 5: Kang et al., Proc. Natl. Acad. Sci. USA 102, 802 (2005)).
Further, the dephosphorylating enzyme PTEN (Phosphatase and tensin homologue deleted on chromosome 10), which catalyzes the reverse reaction of PI3K, inhibits cell proliferation by lowering PIP3 acting as a signal messenger (Non-Patent Document 6: Maehama et al., J. Biol. Chem. 273, 13375-13378 (1998)). With regard to PTEN gene, a deletion or a point mutation is found in many cancers like endometrial cancer and malignant melanoma (Non-Patent Document 7: Salmena et al., Cell 133, 403-414 (2008)), and it has been reported that the dephosphorylating enzyme activity is lowered in most cases of those point mutations (Non-Patent Document 8: Han et al., Cancer Res 60, 3147 (2000)).
In this regard, it is believed that abnormal continuous activation of the PI3K/AKT pathway is caused as a result of these mutations and the signal for cancer cell survival is transmitted.
Thus, PI3K receives attention as an important target molecule for cancer therapy, and development of a PI3K inhibitor is actively performed in recent years. Although several small molecule PI3K inhibitors are at a stage of clinical testing, so far none of them are established as a pharmaceutical product (Non-Patent Document 9: Kong & Yamori, Current Medicinal Chemistry 16, 2839-2854 (2009)).
Meanwhile, it has been known that an abnormality in epigenetics is deeply associated with an occurrence of cancer. Histone acetylation is one of the important mechanisms related to control of epigenetics (Non-Patent Document 10: Carew et al., Giles, Cancer Let 269, 7-17 (2008)), and it is found that, by the inhibition of a histone deacetylase (hereinbelow, referred to as “HDAC”) which resolves the acetylation, a change in gene expression occurs, and cell differentiation or apoptosis occurs accompanying it. For such reasons, the HDAC inhibitor receives attention as a new molecular targeted agents against cancer.
A depsipeptide compound (Patent Documents 1 to 4) is a generic term for a peptide in which at least one amide bond (—CONHR—) is substituted with an ester bond (—COOR). Among the depsipeptide compounds, FK228 (FR901228, also referred to as romidepsin) is a compound isolated as a fermentation product from Chromobacterium violaceum (Non-Patent Document 11: Ueda et al., J. Antibiotics 47, 301 (1994)), and it is a potent HDAC inhibitor which selectively inhibits Class I HDAC (Non-Patent Document 12: Furumai et al., Cancer Res 62, 4916 (2002)). Based on the HDAC inhibiting activity, FK228 as an anti-cancer agent was subjected to a clinical testing, and together with suberoyl anilide hydroxamic acid (SAHA), which is also an HDAC inhibitor, was approved by U.S. FDA as a therapeutic agent for cutaneous T-cell lymphoma.
Meanwhile, although the term “depsipeptide” indicates FK228 in narrow sense, as used herein, it is used as a term having the meaning as described above.
It has been reported that the combined use of a PI3K inhibitor and an HDAC inhibitor results in an increase or synergistic effect in cytotoxic effect in human cancer cell lines (Non-Patent Document 13: Wozniak et al., Haematologica 95, 613 (2010)).
There has been a discussion as to whether or not the HDAC inhibitor itself has an influence on the PI3K/AKT pathway (Non-Patent Document 14: Hanker et al., J Molecular Signaling 4, 5 (2009); Non-Patent Document 15: Graham et al., Clinical Cancer Res 12, 223 (2006)). Trichostatin A (TSA), which is a classic HDAC inhibitor, has been reported to inhibit phosphorylated AKT via protein phosphatase 1 (Non-Patent Document 16: Chen et al., J Biol Chem 280, 38879 (2005)).
With regard to FK228, there is also a report indicating that it inhibits expression of phosphorylated AKT in a cell specific manner (Non-Patent Document 17: Kodani et al., Oncology Reports 13, 477-483 (2005)). However, the mechanism has not been clarified and also there is no document for determining the kinase inhibitory activity of FK228. It is also not reported that depsipeptide compounds have a PI3K inhibitory activity.